Early Cyanosis: Do Not Wait Too Long

Cyanosis is defined as a blue color of the skin and mucous membranes due to at least 3 g/100 mL of reduced hemoglobin in arterial blood (4–6 g/100 mL in capillary blood). A distinction is made between peripheral cyanosis (acrocyanosis), which is confined to the skin of the extremities, and central cyanosis, which includes the tongue and mucous membranes [1]. When central cyanosis is detected early in childhood as an isolated finding—even in the context of an uncomplicated pregnancy, normal growth and physical activity comparable to their peers—comprehensive complementary studies should not be delayed. Here we describe the case of a child with central cyanosis, whose diagnosis was challenging, with progressive clinical deterioration and an uncertain prognosis unless timely treatment was initiated. The patient, a male, was first evaluated at 1 year and 8 months of age for central cyanosis involving the lips, oral mucosa, and extremities. Resting oxygen saturation on room air ranged from 75% to 80%. Despite profound hypoxemia, there were no signs of fatigue or respiratory distress. He had no relevant perinatal history, was born at term with a birth weight of 3200 g and had no prior medical conditions. Family history was noncontributory, aside from parental tobacco use. Physical examination was notable only for visible cyanosis. Laboratory studies revealed isolated polycythemia (hemoglobin 17.7 g/dL; hematocrit 54.6%). At this time, growth had not slowed (weight -0,24 SD, height -0,11 SD). Echocardiography excluded intracardiac right-to-left shunting. Computed tomography pulmonary angiography (CTPA) identified multiple bilateral pulmonary arteriovenous malformations (PAVMs), predominantly located in the left upper lobe (Figure 1). The family reported occasional, self-limited episodes of epistaxis, the clinical relevance of which remained uncertain. Otolaryngological examination revealed nasal mucosal telangiectasias. By the age of four, telangiectatic lesions were also noted on the facial skin and oral mucosa (Figure 2). This patient presents with central cyanosis, mucocutaneous telangiectasias, and resting oxygen saturation ranging from 75% to 80% on room air. Laboratory tests reveal isolated polycythemia. Despite marked hypoxemia, the patient remains clinically asymptomatic. Cardiac causes have been excluded, and CTPA has confirmed the presence of multiple PAVMs. There is no relevant family history. What differential diagnoses should be considered, and what additional investigations are warranted? While the diagnostic workup is ongoing, what therapeutic measures should be initiated? Listen to the Supporting Information S1: Podcast 1 to hear the consortium's decision-making process. The initial suspicion of hereditary hemorrhagic telangiectasia (HHT) was raised based on two Curaçao criteria (mucosal telangiectasias and PAVMs), despite the absence of a relevant family history. Genetic testing revealed no alterations in the genes typically associated with HHT [2, 3]. Familiar study was carried out in the mother and the sister, since the father had died in a traffic accident. As in the patient under study, no HHT mutations were found. The patient underwent multiple catheter-based embolization procedures and received pharmacological treatment—including amlodipine and acetylsalicylic acid—for a limited period, as well as long-term home oxygen. Despite these interventions, there was no significant improvement in blood oxygen saturation, cyanosis, or polycythemia. Follow-up CTPA demonstrated the progressive development of diffuse PAVMs across all lung lobes, with persistent predominance in the left upper lobe. By the age of 5, cyanosis, telangiectasias, and dyspnea had progressed. In the following year, there was a progressive decline in oxygen saturation (from approximately 80% to 65%–70%), everyday activities were severely limited, and digital clubbing began to be evident. Although tacrolimus was considered, it was ultimately not initiated due to uncertainties regarding its potential efficacy in treating PAVMs. Given the progressive clinical deterioration and the lack of effective therapeutic alternatives, the patient was listed for lung transplantation at the age of 6. At this stage of the clinical course, the patient developed a progressively intensifying headache, followed by fever and cold-like symptoms. Two days after the onset of fever, the patient developed seizures, and a cerebral CT scan revealed a left temporal brain abscess. This complication was successfully managed with intravenous antibiotics and surgical drainage (Figure 3). Over the past 2 years, there has been a clear deterioration in the patient's condition. Current symptoms include persistent cough and severe dyspnea with limitation for everyday activities, along with a progressive decline in oxygen saturation (from approximately 80% to 65%–70%), worsening polycythemia, with hemoglobin levels over 24 g/dL, and infectious complications related to the presence of PAVMs, including a brain abscess. What additional treatment options could be considered? Is lung transplantation the most appropriate option at this stage? Listen to the Supporting Information S1: Podcast 2 to hear the consortium's decision-making process. The patient's clinical condition progressively worsened, leading to ICU admission 9 months after the brain abscess, due to type I respiratory failure (oxygen saturation of 70% on a non-rebreather mask at 15 L/min) and respiratory distress. During this hospitalization, the patient experienced two episodes of cardiorespiratory arrest caused by severe hypoxemia secondary to the progression of the underlying disease. As a result, the patient was listed for urgent lung transplantation under high-priority status in March 2020. He required veno-venous extracorporeal membrane oxygenation (ECMO) support for 2 months before undergoing bilateral lung transplantation in May 2020, at the age of 7, with intraoperative central veno-arterial ECMO assistance. Postoperatively, the patient developed several complications (acute cellular rejection treated successfully with steroids, multiple thrombotic events that required anticoagulation that subsequently resulted in a subarachnoid hemorrhage and seizures) which were progressively addressed and resolved. These events prompted cerebral angiography to rule out vascular malformations; no such abnormalities were found. At this point our patient has undergone a successful lung transplant and was discharged with rehabilitation, physiotherapy, immunosuppressive treatment and routine-follow up. Is improvement of the telangiectasia to be expected? What controls should the patient undergo? Listen to the Supporting Information S1: Podcast 3 to hear the consortium's decision-making process. Five years after the transplant, the patient maintains an active lifestyle, engages in sports activities, and reports no respiratory symptoms. Telangiectasias involving the oral and nasal mucosa, as well as the skin, have resolved, along with digital clubbing. Complementary imaging studies have ruled out the presence of vascular malformations in the cerebral and abdominal regions. Current pharmacological management includes tacrolimus, mycophenolate, prednisone, folic acid, and sulfamethoxazole/trimethoprim. Anticonvulsant therapy with levetiracetam and valproic acid is ongoing. The most recent donor-specific antibodies assessment, performed in June 2024, was negative. Hematologic evaluation reveals persistent polycythemia (hemoglobin: 16.5 g/dL; hematocrit: 49.5%) with a slight improvement compared to previous controls. Oxygen saturation levels currently range around 95%. Forced spirometry at 12 years of age showed a forced vital capacity of 62% of the predicted value (z-score: –3.3), with no significant variation compared to prior post-transplant assessments. Reference values were taken from the Global Lung Function Initiative equations [4]. Figure 4 shows the full spirometry report. The test was performed following the current American Thoracic Society/European Respiratory Society standards [5]. A high-resolution chest CT performed during the same timeframe showed normal parenchymal architecture, with no evidence of graft-related complications. Genetic analysis of DNA extracted from the explanted lung tissue identified a somatic PI4KA mutation, consisting in a heterozygous duplication of exons 49-51, as the only relevant finding. The histopathological study reported vascular structures showing a malformed and dilated appearance, with the presence of intimal hyperplasia in the areas of the surgical edge and in large vessels. The small capillary vessels showed thickening of the medial layer, with a hypertensive appearance. Luminal occlusion phenomena and focal areas suggestive of recanalization were also observed. The histological image observed was compatible with HHT (Figure 5). PAVMs are rare in the pediatric population and are almost exclusively observed in individuals with HHT, an autosomal dominant disorder characterized by the development of abnormal vascular structures [2]. Diagnosis of HHT is based on the Curaçao criteria, which include: (1) spontaneous and recurrent epistaxis, (2) mucocutaneous telangiectasias, (3) visceral arteriovenous malformations (such as PAVMs, hepatic AVMs, or cerebral AVMs), and (4) a first-degree relative with a confirmed diagnosis of HHT. The presence of three or more criteria is considered definitive for diagnosis, two criteria are suggestive, and fewer than two make the diagnosis unlikely [3, 6-8]. This patient exhibited two clinical features consistent with HHT—mucocutaneous telangiectasias and diffuse PAVMs—thereby fulfilling two Curaçao criteria. Epistaxis was minimal, limiting its diagnostic weight in a young child. The absence of a positive family history and the lack of pathogenic variants in any of the known HHT-related genes underscore the diagnostic complexity of this case. The discordance between phenotype and genotype raises questions about the broader spectrum of HHT and its potential overlap with other vascular malformation syndromes. The identification of a somatic PI4KA mutation of uncertain significance in the explanted lung tissue introduces new avenues for research into atypical or nonhereditary forms of vascular malformation syndromes. In vitro molecular studies using endothelial cell cultures derived from the patient's explanted lung revealed features of endothelial-to-mesenchymal transition (EndMT), characterized by downregulation of endothelial markers and upregulation of dedifferentiation markers (matrix metalloproteinase 3, fibronectin, vimentin, and the change from VE-cadherin to N-cadherin) [9]. These findings support the hypothesis that the diffuse PAVMs in this patient arose as a consequence of EndMT. There is strong evidence supporting the relevance of EndMT as a key mechanism in AVMs formation. Various studies and models have shown that this process is regulated by TGF-β/BMP signaling pathways, somatic mutations, and epigenetic factors related to chromatin remodeling [10]. Furthermore, mesenchymal markers, such as vimentin, and EndMT-associated factors have been detected in human brain AVMs biopsy samples [11]. The EndMT leading to the severe pattern of PAVMs in our patient may suggest two possible genetic origins. First, a de novo germline mutation may have gone undetected by exome sequencing if located in deep intronic sequences, regulator sequences, or if caused by epigenetic modifications. The other possibility is a somatic mutation, not present in the germ line, but affecting mainly the lung embryonic development. The exclusive detection of the PI4KA mutation in lung tissue supports the latter hypothesis. To date, previous research has not reported any mutations in the PI4KA gene directly related to AVMs. However, PI4KA and PIKfyve form a complex involved in myriad human diseases [12]. Only one study showed that PIKfyve inhibition reduces vascular smooth muscle cell proliferation and migration, useful in restenosis-like processes, but did not mention AVMs as such [13]. Ongoing molecular investigations could shed light in this aspect. The clinical course illustrates the limitations of embolization in the management of diffuse or rapidly progressive PAVMs [8]. Despite multiple embolization procedures and supportive medical therapies, hypoxemia, cyanosis, and polycythemia persisted, leading to progressive clinical decline. This underscores the importance of early identification of refractory cases in which lung transplantation may represent the only curative intervention. The number and caliber of the feeding vessel of the PAVM increase the risk of developing cerebral abscess and thrombosis. Compliance with recommendations to prevent these complications include prophylactic antibiotic with dental procedures, use of filter devices in vascular lines, and avoiding scuba diving [14]. Successful bilateral lung transplantation in an 18-year-old female with extensive PAVMs, cerebral and hepatic AVMs, was followed by partial or complete resolution, respectively, during the second year after transplantation [15]. Immunosuppressive therapy included tacrolimus, mycophenolate mofetil and prednisolone (data provided by the first author). In our case, although tacrolimus was not administered before transplantation, its inclusion in the post-transplant immunosuppressive regimen coincided with complete resolution of mucocutaneous telangiectasias and the absence of new visceral AVMs over a 5-year follow-up period. While anecdotal, this observation raises the possibility that calcineurin inhibitors may modulate angiogenic pathways implicated in AVMs development and persistence, as suggested by experimental models. In vitro studies have shown that tacrolimus increases ENG and ALK1 RNA and protein expression, potentially mitigating the effects of protein haploinsufficiency seen in HHT [16]. Furthermore, clinical trials in HHT patients have demonstrated symptomatic improvement—particularly in epistaxis and gastrointestinal bleeding—with tacrolimus therapy [17, 18]. Prospective studies are warranted to evaluate the potential role of tacrolimus as a disease-modifying agent in AVM syndromes. The pre-transplant course in our patient was further complicated by severe hypoxemia requiring ECMO support. Post-transplant complications included acute cellular rejection, thrombotic events, and neurological sequelae such as subarachnoid hemorrhage. Despite these challenges, the overall benefit of bilateral lung transplantation was evident, with sustained respiratory improvement and resolution of mucocutaneous telangiectasias. Lung transplant is a challenging decision, and should be individualized considering the clinical progression and quality of life, the risk of complications with likely severe sequelae associated with PAVMs, the willingness of the patient and/or her parents as it was in our patient, the longer survival of patients with HHT who refused lung transplant compared with that of those transplanted with all type of diseases, and the availability of lung donors in each particular country [19]. Furthermore, the absence of AVMs in other organs should also be considered, as it may facilitate the decision-making process for lung transplantation. Conversely, their presence may raise concerns when evaluating transplantation, although we think it should not be considered an absolute contraindication. The clinical condition of the patient and the risk–benefit balance should always be assessed on an individual basis. This case of bilateral PAVMs highlights several important considerations that warrant reflection when facing similar patients. The diagnostic process in pediatric PAVMs requires a high index of suspicion, particularly when clinical features only partially fulfill diagnostic criteria for syndromic conditions such as HHT. In these cases, early multidisciplinary evaluation is essential to achieve an accurate diagnosis and guide timely therapeutic planning. Early administration of tacrolimus might be considered following diagnosis, given its association with regression of mucocutaneous telangiectasia and the positive results from both in vitro and in vivo studies. Lung transplantation should be considered when embolization fails to improve oxygenation, ideally before the onset of severe complications such as cerebral abscess or cardiorespiratory arrest. Finally, after a successful transplantation, long-term follow-up should include monitoring for graft-related complications as well as the potential development of AVMs in other organs. Carmela Galley-Martín: conceptualization, writing – original draft, writing – review and editing, supervision, methodology, validation. Luisa María Botella-Cubells: conceptualization, investigation, writing – original draft, writing – review and editing, conceptualization, writing – original draft, writing – review and editing, supervision, conceptualization, writing – original draft, writing – review and editing, investigation, investigation, investigation, investigation, The of review of this case in with In with the all relevant standards were The with the the of the of and current and for was from the patient's patient is activities at the were and by the under number The no of The that support the findings of this study are from the The is not for the or of any supporting by the than should be to the for the Diagnosis and What differential diagnoses should be considered, and what further investigations are While the diagnostic workup is ongoing, what therapeutic measures should be initiated? 1 from which has been ruled pulmonary causes such as lung should be However, in the absence of other clinical persistent hypoxemia with cyanosis and polycythemia is more suggestive of a right-to-left 2 is consistent with While differential diagnoses or should be considered, the clinical is by a right-to-left shunting. 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